EP1919436B1 - Material primarily for medical, long-term in vivo use, and method for the production thereof - Google Patents

Abstract

The invention relates to a material that is used primarily for medical, long-term in vivo purposes, e.g. as a filling material in dentistry. The aim of the invention is to create a material primarily for medical, long-term in vivo use which does not have the disadvantages of materials used in prior art, does not release active substances, and endures after the material has been removed or when the shape thereof is modified. The aim is achieved by the fact that the material is made of polymers and filling agents which are embodied as polymer-coated, chemically modified particles that carry hydroxyl groups and are surrounded by a matrix of another polymer. The coating polymer develops an antimicrobial effect.

Description

The invention relates to a material for predominantly medical, long-term in vivo use, such as. As a filling material in dentistry and a method for its preparation.

It is known that exogenous materials used in the body (for example in the oral cavity) or on the body (for example as a catheter) are exposed to the microorganisms present there or can promote the penetration of microorganisms into the body.

This is, for example, in the oral cavity to an aerobic or anaerobic mixed flora. The most frequently occurring bacterial strains include the caries-inducing Streptococcus mutans [ Hellwig E et al. Introduction to tooth preservation. Urban & Schwarzenberg Verlag, Munich 1995 ] and as a first colonizer the Streptococcus sanguis.

Commonly used in the oral cavity materials include metals, ceramics, polymers or mixed materials, so-called composites. Eichner K. Dental materials and their processing. Volume 1, Volume 2. Hüthig Verlag Heidelberg 1988 and Craig GC, Powers JM. Restorative Dental Materials. 11th ed. Mosby, St. Louis 2002 ].

Of all the known dental materials, the composites, which are used as fixing materials or filling materials, have the reputation of favoring bacterial deposits in the oral cavity [ Weitmann RT, Eames WB. Plaque accumulation on composite surfaces after various finishing procedures. J Am Dent Assoc 1975; 91: 101-106 ; Skorland KR, Sonju T. Effect of sucrose rinses on bacterial colonization on amalgam and composite. Acta Odontol Scand 1982; 40: 193-196 and Svanberg M, et al. Mutans streptococci in plaque from margins of amalgam, composite, and glass-ionmer restorations. J Dent Res 1990; 69: 861-864 ]. To make matters worse, that composites shrink when polymerizing, thereby filling or cement joints Micro-fine gaps between tooth substance (dentin / enamel) and the composite can arise. Bacteria can colonize this fine cleft successfully [Hellwig E et al. Introduction to tooth preservation. Urban & Schwarzenberg Verlag, Munich 1995].

Since these spaces are largely removed from the teeth cleaning and the rinsing effect of the saliva, the bacteria multiply undisturbed and lead after a short time to the development of carious lesions. Bacteria can not only colonize materials, they can also use some of the carbon content of the polymers for their metabolism and thus contribute to the degradation of the composites [and Craig GC, Powers JM. Restorative Dental Materials. 11th ed. Mosby, St. Louis 2002 ].

Bacteria thus harm in two ways: on the one hand, their undisturbed multiplication leads to tooth decay and on the other hand they contribute to the gradual destruction of the material.

The release of active ingredients from medically applicable materials has been known for several decades. Application sites are u.a. Blood vessels (drug-releasing from coated stents for vascular dilation) or bone (in bone infections implantation of a polymer bead chain of polymethyl methacrylate (Septopal® the company biometmerck) with the antibiotic gentamycin (Refobacin® Merck).

If artificial hip joints are implanted via a "cementation", the "cement" (hardening polymer compound) is also treated with an antibiotic in this procedure.

While the release from the stents should prevent restenosis, ie the growth of the vessel, the ball chains are used in existing infections. In the case of hip implantation, the antibiotic is used prophylactically to prevent the onset of infection.

In the oral cavity systems are used with active ingredients in the form of mouthwashes, toothpastes [ Lahdenpera MS, Puska MA, Alander PM, Waltimo T, Vallittu PK. Release of chlorhexidine diglugonate and flexural properties of glass fiber reinforced provisional fixed partial denture polymer. J Mat Sci Mat Med 2004; 15: 1349-1353 ; Imazato S. Influence of incorporation of antibacterial monomer on curing behavior of a dental composite. J Dent 1999, 27: 292-297 ; Imazato S, Torii M. Incorporation of bacterial inhibitor into resin composite. J Dent Res 1994; 73: 1437-1444 and Addy M, Handley R. The effect of the incorporation of chlorhexidine acetate on some physical properties of polymerized and plasticized acrylics. J Oral Rehabil 1981; 8.155-163 ].

One of the most common oral antibacterial agents is chlorhexidine digluconate [ Lahdenpera MS, Puska MA, Alander PM, Waltimo T, Vallittu PK. Release of chlorhexidine diglugonate and flexural properties of glass fiber reinforced provisional fixed partial denture polymer. J Mat Sci Mat Med 2004; 15: 1349-1353 ]. In applications over more than six weeks it comes to mucous membrane discoloration and taste irritation, which is why a long-term medication does not make sense.

Dental amalgams are known to make it difficult or impossible for microorganisms to survive the release of volatiles such as copper in the filling gap [ Skorland KR, Sonju T. Effect of sucrose rinses on bacterial colonization on amalgam and composite. Acta Odontol Scand 1982; 40: 193-196 and Svanberg M, et al. Mutans streptococci in plaque from margins of amalgam, composite, and glass-ionmer restorations. J Dent Res 1990; 69: 861-864 ].

For composites, concepts are discussed in which the incorporation of releasable bactericidal substances reduces or even prevents plaque accumulation [ Imazato S. Influence of incorporation of antibacterial monomer on curing behavior of a dental composite. J Dent 1999, 27: 292-297 and Imazato S, Torii M. Incorporation of bacterial inhibitor into resin composite. J Dent Res 1994; 73: 1437-1444 ].

The disadvantage of all preceding solutions, however, is that many of the substances in question with antibiotic activity can develop allergic or toxic effects. In addition, in the known materials (eg cement or filling) it must be ensured that over the entire residence time of the Material in the oral cavity a sufficient drug level is guaranteed.

As antibacterial substances in addition to the synthetically produced antibiotics also substances are used, which are derived from natural products. These include u.a. Chitosan and its derivatives.

The writings EP 0329098 B1 . EP 0389629 B1 . EP 1255576 B1 and EP 1237585 B1 disclose curable pastes of various oxides or phosphates and chitosan as a binder, wherein the chitosan is reduced by the basic properties of the oxides in its solubility. The described application in the dental field relates to root filling materials or due to the lack of stability against the pH in the mouth only on provisional filling materials.

From the Japanese script 02102165 A is a chitosan and hydroxylapatite containing mass is known, which can be used as a ceramic only after sintering.

The disadvantage of this solution is that in the sintering, acting as a binder, organic components are pyrolyzed.

The writings EP 0287105 B1 and EP 1296726 B1 disclose an osteogenic implant material of a glycosaminoglycan with cationic polymers as matrix substances, in which filler particles of bone-like composition are incorporated. Although chitosan is a glycosaminoglycan, the abovementioned claims explicitly describe a body-resorbable bone substitute material that can also be used in the area of the jaw.

The Japanese script 07157434 A describes a proliferation inhibitor for oral bacteria formed by chitosan and its derivatives.

From the Japanese writing 10130427 A For this purpose, the addition of metal ions to the amino groups of chitosan or its derivatives is known, this system is used with hydroxyapatite.

A similar material of chitosan derivatives and stannous fluoride is disclosed in Japanese Publication 05000930A.

To date, chitosan is used only in conjunction with bioresorbable fillers, such as. Calcium phosphate and serves as a degradable bone filler or as a temporary tooth filling material. Chitosan is used as a binder because of its pH-dependent solubility.

The disadvantage of all known materials is that they do not have a stable antimicrobial effect for long-term in vivo use.

The invention is therefore based on the object of specifying a material for predominantly medical, long-term in vivo use, which avoids the disadvantages of the prior art and is initiated without an active agent releasing and after the removal of the material or despite changing the material shape continues persists. In addition, a method for producing this material should be specified.

According to the invention, this object is solved by the characterizing features of the first claim and supplemented by advantageous embodiments according to the subclaims.

The essence of the invention is that a polymer-based material is provided, which, in a medical application in the oral cavity, for example as a filling or cement, exhibits an antimicrobial / antibacterial effect during the entire residence time without being toxic or allergic. In this case, this effect continues even after the removal of material or after damage.

Advantageously, the material consists of packing in the form of polymers, copolymers, composites, metals, glass-like compounds, ceramics in pure form or as mixtures of these materials, with a polymeric view in the form of polysaccharides or their Derivatives coated, these polymeric coatings have an antimicrobial effect and the coated Füllköper are surrounded by a matrix consisting of a further polymer.

Particularly advantageous is this polysaccharide chitosan.

According to the invention, the polymer, for example in the form of chitosan, is modified by deacetylation in such a way that the deacetylated polymer, for example the chitosan, can be coupled to a modified silicon dioxide particle surface (terminal aldehyde groups on the particle surface) and subsequently thereto Coupling of 3-vinylbenzaldehyde to the polymer-coated particles can take place.

In addition, this antimicrobial coating may be chemically modified to introduce carbon-carbon (double) bonds that participate in the chemical reaction (e.g., polymerization) in the curing process.

In addition, the additional chemical modification can be used to change the dispersion behavior, to immobilize activatable starter molecules (initiators which are activatable, for example, chemically, thermally or under UV light) on the surface or for the chemical reaction (for example the. Polymerization) to immobilize necessary or additional reaction accelerators or regulators for adjusting the chain length on the surface.

This filler thus activated is dispersed in a liquid monomer mixture, for example bis-GMA, TEGDMA, UDMA, BPO, camphorquinones or ketones, so that the material according to the invention is obtained.

The coating according to the invention of the polymer particles produces an antibacterial effect which lasts for longer periods of time, at the same time causing the connection to the polymer matrix and the associated improved dispersion of the particle powder in the liquid phase

When dispersed, the terminal vinyl group of the particles (activated fillers) reacts with the monomers to form a polymer matrix. The activated filler is thus in consequence of chemical bond integrative component of the material according to the invention.

The invention will be explained in more detail below with reference to the embodiment.

1. Deacetylation of chitosan:

The deacetylation of chitosan is carried out according to the known method under reflux in hydrochloric acid. The thus deacetylated chitosan is purified according to the prior art by a dialysis process and converted by freeze-drying in a solid form.

2. Coupling of Deacetylated Chitosan to Modified Silica Particle Surfaces / Coupling of 3-Vinylbenzaldehyde:

The hydroxyl groups of silica particles are reacted with 3-aminopropyltriethoxysilane in a mixture of ethanol / water at 45 ° C.

After purification of the particles / fillers by rinsing with ethanol, the amino groups are modified with glutaraldehyde at room temperature to form a Schiff base and then rinsed with water. This gives a terminal aldehyde group on the silica particles / packings which is reacted with an aqueous solution of deacetylated chitosan at room temperature.

The chitosan-modified particle surface / packing surface is reacted with 3-vinylbenzaldehyde. The excess amino groups of the chitosan react with the 3-vinylbenzaldehyde to form a Schiff base. The particles / packing are cleaned of non-covalently bonded 3-vinylbenzaldehyde by rinsing several times with water and then dried.

By this process, the powder (s) have covalently bound chitosan on its surface, the amino groups of which are chemically modified in part by the reaction with 3-vinylbenzaldehyde.

To prepare the material, the modified powder (s) are dispersed in the monomer mixture (e.g., bis-GMA, TEGDMA, UDMA, BPO, camphorquinones, or ketones). The terminal vinyl group of the particles / packing reacts with the monomers in the reaction (hardening of the filler) to the polymer matrix. The activated filler is thus chemically incorporated in the polymer and forms with this the material according to the invention.

3. Evidence of antibacterial activity was provided by bacterial attachment tests.

To demonstrate the chemical integration of the packing to the polymer matrix, dynamic mechanical tests (DMA) and bending tests are carried out.

For this purpose, test specimens (for example in the form of platelets) are produced using the material according to the invention.

As a reference, for example, a material with unmodified powder / packing according to the prior art used. The proportions of the powder / filler in the filler are known to be 20-30% by volume.

The specimens are exposed to a suspension of bacteria (eg Streptococcus sanguis ) . The bacteria thus have the opportunity to accumulate on the sample surface and multiply.

After 36 hours, the superficially occurring bacterial counts in the material according to the invention are detected quantitatively by means of fluorescence method and scanning electron microscope and compared with the bacterial counts of the reference.

All features described in the description and the following claims may be essential to the invention both individually and in any combination with one another.

Claims (4)

1. Material consisting of a polymer matrix and antimicrobial filling agents for primarily medical, long-term in vivo purposes, wherein the filling agents are silicon dioxide particles coated by an antibiotic polysaccharide, and said particles carry terminal vinyl groups by means of which the filling agents are incorporated into the polymer matrix.
2. Material in accordance with claim 1, wherein the polymer coating of the particles comprises chitosan.
3. Material in accordance with claim 1, wherein the polymer matrix is formed monomers selected from bis-GMA, TEGDMA, UDMA, BPO, campherchinone or ketones.
4. Method for producing a material according claim 2 or 3, comprising the following steps:

   • reacting 3-aminopropyl-triethoxysilan with hydroxyl group-carrying silicon dioxide particles in a mixture of ethanol/water thereby to form amino groups on the particles,

   • reacting glutaraldehyde with the amino groups, forming a Schiff base, thereby to form terminal aldehyde groups on the silicon dioxide particles,

   • coating the particles having terminal aldehyde groups with deacetylated chitosan,

   • reacting the coated particles with 3-vinyl benzaldehyde thereby to chemically modify the coating; and

   • dispersing the chitosan-coated, chemically modified particles in a monomer mixture and then polymerizing the monomer matrix thereby to form a polymer matrix.